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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disorder of muscle in children, with an incidence of approximately 1 in 3,300 male births. In about a third of affected boys, the disease is due to a new mutation, and most patients die in their early 20s. Over the last few years, the genetic, biochemical and histopathological basis of DMD has been elucidated greatly. In particular, the discovery of "dystrophin," the protein product of the DMD gene is truly an epoch-making success in the history of muscular dystrophy research. Dystrophin is now thought to be a cytoskeletal protein underlying the plasma membrane (known in muscle as the sarcolemma) of normal muscle fiber, and is undetectable or greatly reduced in DMD. In this review article, dystrophin in normal skeletal muscle and various neuromuscular diseases including DMD/BMD (Becker muscular dystrophy), and its carrier is discussed.
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PMID:Dystrophin abnormality in progressive muscular dystrophy--a review article. 195 48

The gene for Duchenne (DMD) and Becker (BMD) types of muscular dystrophy has been isolated by Kunkel's and Worton's groups and shown to be the largest one over known in human, spanning more than 65 exons distributed over 2,500 kb in P21 region of X-chromosome. Fourteen kb cDNA encodes 427 kD cytoskeletal protein "dystrophin", supposed to form an anti-parallel homodimer like alpha-actinin and spectrin. The polyclonal antibodies against the synthetic peptides or fusion proteins predicted from dystrophin cDNA disclosed the complete absence of dystrophin at the surface membrane of both skeletal and cardiac muscles of DMD in marked contrast with the continuous and uniform staining in normal muscles. In manifested carriers, the mosaic expression of dystrophin was observed at the surface membrane of the skeletal muscle. BMD, which is thought to be allelic to DMD, revealed a faint or patchy immunostaining along with the abnormal and/or lower amount of dystrophin. In BMD, there is an intimate connection between the amount of dystrophin and the severity of the clinical course. It should be noted that 5 out of 39 patients with clinical diagnosis of limb-girdle (L-G) muscular dystrophy showed a patchy staining pattern, suggesting BMD not L-G. On the basis of dystrophin discovery, a possible therapeutic trial of DMD is discussed.
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PMID:[Molecular pathology of Duchenne and Becker muscular dystrophy]. 209 74

1. Attachment to extracellular matrix is thought to be particularly important for striated muscle cells, since skeletal and heart muscle have to withstand considerably strong forces. 2. We have recently shown that a defect in a protein of the muscle basement membrane, M-laminin, is correlated with muscular dystrophy in human and mouse. The disease associated with defects in M-laminin is thus analogous to that caused by defects in the cytoskeletal protein, dystrophin, the Duchenne/Becker muscular dystrophy. 3. One may propose the hypothesis that a pathway of interacting proteins is required to connect the cytoskeleton of the muscle fiber to the extracellular matrix, and that a defect in any protein in this chain would result in severe impairment of muscle cell attachment with resulting muscle damage upon use of the muscle. The existence of such chains of proteins may be expected from known mutations in muscle proteins in Drosophila and Caenorhabditis elegans. Some of these mutations cause phenotypes resembling muscular dystrophy in mammals. 4. It will be important to identify all the proteins that are participants in muscle cell attachment, including receptors for M-laminin and proteins associated with these receptors.
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PMID:Cell adhesion in muscle. 778 6

Mutations in the dystrophin gene cause the X chromosome-linked, recessive Duchenne and Becker muscular dystrophies. Dystrophin, a large cytoskeletal protein, copurifies with a complex of dystrophin-associated proteins which serve to anchor dystrophin to the sarcolemma. One of these associated proteins, adhalin, has been implicated as a candidate for severe childhood autosomal recessive muscular dystrophy (SCARMD) due to absence of anti-adhalin staining in muscle biopsy samples taken from SCARMD patients. Furthermore, the Duchenne-like dystrophic phenotype seen in the SCARMD families was shown to be tightly linked to chromosome 13 markers. To determine the genetic mutation responsible for autosomal dystrophy, we characterized the human adhalin gene. Contrary to our expectation, human adhalin was mapped to chromosome 17q21, excluding adhalin as the gene causing chromosome 13-associated SCARMD. Additionally, a splice form of adhalin message was found that predicts a 35-kDa nontransmembrane adhalin. The expression of both adhalin splice forms is exclusively restricted to striated muscle, unlike other components of the dystrophin-glycoprotein complex.
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PMID:Human adhalin is alternatively spliced and the gene is located on chromosome 17q21. 793 74

Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is a cytoskeletal protein tightly associated with a large oligomeric complex of sarcolemmal glycoproteins including dystroglycan, which provides a linkage to the extracellular matrix component, laminin. In DMD, the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins, causing the disruption of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix which, in turn, may render muscle cells susceptible to necrosis. The COOH-terminal domains (cysteine-rich and carboxyl-terminal) of dystrophin have been suggested to interact with the sarcolemmal glycoprotein complex. However, truncated dystrophin lacking these domains was reported to be localized to the sarcolemma in four DMD patients recently. Here we report that all of the dystrophin-associated proteins are drastically reduced in the sarcolemma of three DMD patients in whom dystrophin lacking the COOH-terminal domains was properly localized to the sarcolemma. Our results indicate that the COOH-terminal domains of dystrophin are required for the proper interaction of dystrophin with the dystrophin-associated proteins and also support our hypothesis that the loss of the dystrophin-associated proteins in the sarcolemma leads to severe muscular dystrophy even when truncated dystrophin is present in the subsarcolemmal cytoskeleton.
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PMID:Deficiency of dystrophin-associated proteins in Duchenne muscular dystrophy patients lacking COOH-terminal domains of dystrophin. 834 21

Dystrophin is a large cytoskeletal protein encoded by the Duchenne muscular dystrophy (DMD) gene. Dystrophin is associated with a large oligomeric complex of sarcolemmal glycoproteins, including the novel laminin-binding glycoprotein called dystroglycan, which provides a linkage to the extracellular matrix. In DMD, the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins. In severe childhood autosomal recessive muscular dystrophy with DMD-like phenotype (SCARMD), a specific deficiency of the 50 kDa dystrophin-associated glycoprotein is found. Thus, the disruption/dysfunction of the dystrophin-glycoprotein complex due to the deficiency of one or more of the dystrophin-associated proteins is presumed to cause the disruption of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix. This may render muscle cells susceptible to necrosis in two forms of severe childhood muscular dystrophy, DMD and SCARMD.
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PMID:Deficiency of dystrophin-associated proteins: a common mechanism leading to muscle cell necrosis in severe childhood muscular dystrophies. 835 36

Deletions and point mutations in the gene encoding the cytoskeletal protein dystrophin and its isoforms cause either the severe progressive myopathy Duchenne muscular dystrophy (DMD) or the milder Becker muscular dystrophy (BMD), largely depending on whether the reading frame is lost or maintained respectively. Frameshift mutations tend to result in a lack of dystrophin at the sarcolemma, destabilization of the membrane and degeneration of skeletal muscle. The mdx mouse is a valuable animal model of DMD as it bears a nonsense point mutation in exon 23 of the murine DMD gene leading to an absence of dystrophin expression in the muscle sarcolemma and muscular dystrophy. This report represents a novel approach to correct dystrophin deficiency at the post-transcriptional level by transfection of muscle cells with antisense RNA. Essentially, 2'- O -methyl oligoribonucleotides (2'OMeRNA) were delivered to the nuclei of primary mdx myoblasts in culture. Dystrophin expression was observed in the sarcolemma of transfected mdx myotubes after transfection by an oligonucleotide complementary to the 3' splice site of murine dystrophin intron 22. Direct sequencing of RT-PCR products from these cells revealed precise splicing of exon 22 to exon 30, skipping the mutant exon and creating a novel in-frame dystrophin transcript. As patients with comparable in-frame internal deletions show relatively mild myopathic symptoms, this may in the future offer a therapeutic approach for DMD, as well as for other inherited disorders.
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PMID:Modification of splicing in the dystrophin gene in cultured Mdx muscle cells by antisense oligoribonucleotides. 961 64

In Duchenne muscular dystrophy (DMD) and its murine model, the dystrophic mouse (MDX), the skeletal musculature lacks dystrophin. The presumed function of this cytoskeletal protein is to protect the sarcolemma against mechanical stress during muscle activity. To test this hypothesis in vivo, we bred a double mutant mouse that combines two genetic defects: the dystrophin-deficiency of the MDX mouse and the Cl- channel myotonia of the arrested development of righting response (ADR) mouse. We hypothesized that high mechanical muscle activity would aggravate muscular dystrophy in double mutant ADR-MDX mice. On the contrary, ADR-MDX mice showed fewer signs of muscle fiber necrosis and fibrosis than MDX mice at all ages. Plasma creatine kinase levels were slightly increased in ADR-MDX, but significantly lower when compared to MDX mice. Sections of ADR-MDX muscle showed a uniform pattern of oxidative muscle fibers. Similar findings have been obtained in dystrophin-positive ADR mice, they result from a complete fiber-type IIB to IIA transformation in myotonic muscle. Our results suggest that small, oxidative fibers of myotonic mice are less sensitive to dystrophin deficiency. Therefore, ADR-MDX mice develop less severe muscular dystrophy than MDX mice do, although their muscles are continually stressed. The new ADR-MDX double mutant mouse is the first animal model combining both a dystrophinopathy and a channelopathy. The results presented here give new insights into the pathomechanism of muscular dystrophy and may be helpful for the therapeutic management of DMD.
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PMID:Myotonic ADR-MDX mutant mice show less severe muscular dystrophy than MDX mice. 1009 60

p94, a muscle-specific member of the calpain family, also called calpain3 (CAPN3), has been identified as the gene product responsible for limb-girdle muscular dystrophy type 2A (LGMD2A). To elucidate the molecular mechanism of LGMD2A, the effects of missense point mutations found in LGMD2A on the unique properties of p94 were studied. All of the mutants examined to date lose their proteolytic activity against fodrin, a cytoskeletal protein, strongly suggesting that of the specific properties of p94, the loss of protease activity is the prime cause of LGMD2A. Studies of LGMD2A and p94 suggest a novel molecular mechanism for muscular dystrophy, showing that a combined pathologic and biochemical approach is effective.
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PMID:New aspect of the research on limb-girdle muscular dystrophy 2A: a molecular biologic and biochemical approach to pathology. 1063 25

The utrophin gene codes for a large cytoskeletal protein closely related to dystrophin, the gene mutated in Duchenne's muscular dystrophy. Although utrophin could functionally substitute for dystrophin, in Duchenne's muscular dystrophy patients it did not compensate for the absence of dystrophin because in adult muscle utrophin was poorly expressed and limited to subsynaptic nuclei. However, increased levels of utrophin have been observed in regenerated muscles fibers suggesting that utrophin up-regulation in muscle is feasible. We observed that utrophin mRNA was transiently up-regulated at early time points after muscle injury with a peak already 24 h after muscle damage and utrophin induction in activated satellite cells before fusion into young regenerated fibers. Injection of utrophin lacZ constructs into regenerating muscle demonstrated that the utrophin upstream promoter under the control of its intronic enhancer activated the transcription that leads to the expression of the reporter gene in the newly formed fibers, which was not limited to neuromuscular junctions. Utrophin enhancer activity was dependent on an AP-1 site, and in satellite cells of regenerating muscle the AP-1 factors Fra1, Fra2, and JunD were strongly induced. These results establish that utrophin was induced in adult muscle independently from neuromuscular junctions and suggest that growth factors and cytokines that mediate the muscle repair up-regulate utrophin transcription.
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PMID:The utrophin gene is transcriptionally up-regulated in regenerating muscle. 1187 58


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